CZ299518B6 - Pharmaceutical compositions containing Xa factor inhibitor in combination with anti-platelet aggregation agent - Google Patents

Abstract

The present invention relates to the use of direct or indirect selective inhibitors of factor Xa acting via antithrombin III, alone or in combination with one or more compounds exhibiting anti-platelet aggregation activity, for the preparation of medicaments intended to prevent and to treat thromboembolic arterial diseases. There are also disclosed pharmaceutical compositions containing one or more direct or indirect selective factor Xa inhibitors, which act through the mediation of antithrombin III in combination with one or more compounds with anti-platelet aggregation activity, and optionally one or more pharmaceutically acceptable vehicles.

Description

Technical field

The present invention relates to the use of indirect factor Xa inhibitors which act via antithrombin III, in combination with a platelet aggregation active compound, for the preparation of medicaments for the prevention and treatment of vascular thromboembolic diseases.

The present invention also provides pharmaceutical compositions comprising a combination of an antithrombotic component and a component that is active against platelet aggregation. The active ingredients forming the combination are present in the free state or in the form of one of the pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION

In the last decade, much attention has been paid to the role of platelets in the development of atherosclerosis-related diseases (myocardial infarction, tonsillitis, stroke, lower limb vascular disease and the like). Furthermore, the well-known role of the blood clotting process in arterial thrombosis has allowed the development of many drugs that inhibit various clotting enzymes. The discovery of the basic role of thrombin and factor Xa in the thrombotic process has led to the use of anticoagulants, which are expected to act preventively and therapeutically in arterial thrombosis.

Among the available anticoagulants, heparin is the preferred drug in the prevention and treatment of thromboembolic diseases.

In particular, heparin catalyzes, through antithrombin III (AT III), the inhibition of two enzymes involved in the blood coagulation cascade, in particular factor Xa and factor IIIa (or thrombin). The mutual importance of these two activities relative to the total heparin activity remains unknown. Low molar mass heparin (LMWH) compositions contain chains of 4 to 30 monosaccharides which act as heparin to factor Xa and thrombin but which are more selective for factor Xa than for thrombin. Despite this different biological activity profile, low molar mass heparin has an antithrombotic effect, as demonstrated in animal studies and in patients suffering from thromboembolic diseases or at risk of developing thrombus (Hirsch J. et al., J. Tromb. Hemost., 1987, Leuven , Belgium Leuven University Press, 325-348).

Unlike heparin and LMWH, some synthetic oligosaccharides, particularly those described in EP 84999, have properties that allow selective Xa inhibition by antithrombin III, but have no activity with respect to thrombin. These synthetic oligosaccharides, which correspond to the heparin antithrombin (ABD) binding domain, are known and exhibit anti45 thrombotic activity in vascular thrombosis. These compounds are described in EP 529715 and EP 621282.

The effectiveness of these oligonucleotides in preventing arterial thrombosis was very unlikely due to the inability to inhibit thrombin.

However, it has long been known in the literature that thrombin plays a key role in arterial thrombosis, which has also been confirmed by recent experiments (L. A. Harker, Blood, 1991, 77, 1006-1012). Therefore, thrombin inhibitors provide an effective method of preventing or suppressing this type of thrombosis.

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When comparing the efficacy of heparin with that of direct thrombin inhibitors (direct inhibitor means an inhibitor that inhibits thrombin without the need for AT III), they have been found to be far more effective than heparin in the prevention and treatment of arterial thrombosis (Arteriosclerosis and thrombosis, 1992, 12, 879-885 (J. Am. Coli. Cardiol., 1994, 23, 993-1003). The reason for this loss of efficacy is that the heparin / AT III complex cannot, due to steric hindrance, inhibit thrombin in the formation of thrombus in platelets, thereby forming a platelet thrombus.

Low heparin activity compared to direct inhibitors is therefore associated with the need for AT III. This explanation is further supported by the recent finding that direct factor Xa inhibitors that function without AT III are also effective in an animal model of arterial thrombosis (Circulation, 1991, 84, 1741-1748 Trombosis Haemost., 1995 74, 640-645 ).

It would be expected that a compound that acts through AT III on the one hand and does not inhibit thrombin on the other hand is not active in arterial thrombosis.

Surprisingly, according to the present invention, it has been found that a direct or indirect selective factor Xa inhibitor, alone or in combination with a compound having anti-platelet aggregation activity, can be used in the treatment of thromboembolic diseases of arterial origin.

Although anti-Factor Xa agents and platelet aggregation agents are known to function through two different mechanisms, the combination or combination of these products for use in arterial thromboembolic diseases has never been studied.

SUMMARY OF THE INVENTION

Thus, one object of the present invention is the use of an oligosaccharide which is an indirect factor Xa inhibitor acting through antithrombin III, in combination with one or more compounds having anti-platelet aggregation activity, antagonizing glycoprotein IIb / IIIa and selected from the group consisting of:

- ethyl N- (1-ethoxycarbonylmethylpiperidin-4-yl) -N- {4- [4 - {(N-ethoxycarbonylimino) (amino) methyl} phenyl] thiazol-2-yl} -3-aminopropionate,

-N- (1-carboxymethylpiperidin-4-yl) -N- {4- [4 - {(amino) (imino) methyl} phenyl] thiazol-2-yl} -3-aminopropionic acid, and its pharmaceutically acceptable salts, for the preparation of drugs intended for the prevention and treatment of thromboembolic arterial diseases.

According to the present invention, a selective factor Xa inhibitor is a compound capable of selectively inhibiting factor Xa by antithrombin (AT III) but not showing significant activity with respect to thrombin.

In another embodiment, the invention provides a pharmaceutical composition comprising an oligosaccharide that is an indirect factor Xa inhibitor acting through antithrombin III, in combination with one or more compounds having anti-platelet aggregation activity, antagonizing glycoprotein IIb / IIIa and selected from the group consisting of:

- ethyl N- (1-ethoxycarbonylmethylpiperidin-4-yl) -N- {4- [4 - {(N-ethoxycarbonylimino) (amino) methyl} phenyl] thiazol-2-yl} -3-aminopropionate,

-N- (1-carboxymethylpiperidin-4-yl) -N- {4- [4 - {(amino) (imino) methyl} phenyl] thiazol-2-yl} -5-aminopropionic acid, and pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable carriers.

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Indirect selective factor Xa inhibitors and preferably synthetic oligosaccharides include pantasaccharides such as those claimed in patents EP 84 999 and US 5 378 829.

Particularly preferred pentasaccharides are:

methyl-O- (2-deoxy-2-sulfoamino-6-O-sulfo-α-D-glucopyranosyl) - (1-> 4) -O- (3-D-glucopyranosyluronic acid) - (1-> 4) -O - (2-deoxy-2-sulfoamino-3,6-di-O-sulfo-α-D-glucopyranosyl- (1-> 4) -O- (2-O-sulfo-α-L-idopyranosyluronic acid) - (1-> 4) -2-deoxy-2-sulfoamino-6-sulfo-α-D-glucopyranoside, whose anion has the structure B

and pharmaceutically acceptable salts thereof, particularly the decasic salt, known under the code name SR 90107 / ORG 31540, which is described in Chemical Synthesis to Glycoaminoglycans, Supplement to Nature 1991, 350, 30-33, hereinafter referred to as "PS";

methyl-O- (3,4-di-o-methyl-2,6-di-O-sulfo-α-D-glucopyranosyl) - (1-> 4) -O- (3-O-methyl 12-O-sulfo) -3-D-glucopyranosyluronic acid) - (1-> 4) -D- (2,3,6-tri-O-sulfo-α-D-glucopyranosyl- (1-> 4) -O- (3-O-methyl) -2-0-sulfo-α-L-idopyranosyluronic acid) - (1-> 4) 2,3,6-tri-O-sulfo-α-D-glucopyranoside known under the code name SANORG 32701, whose anion has the structure C

and its pharmaceutically acceptable salts, especially dodecasodium salt, as described in US 5,378,829; 25 methyl-O- (2,3,4-tri-O-methyl-6-O-sulfo-α-D-glucopyranosyl) - (1-> 4) -O- (2,3-di-Omethyl-PD-glucopyranose) 1-uronic acid) - (1-> 4) -O- (2,3,6-tri-O-sulfo-α-D-glucopyranosyl- (1-> 4) -O- (2,3-di-O-methyl) -aL-idopyranosyluronic acid) - (1-> 4) -O-2,3,6-tri-O-sulfo-α-D-glucopyranoside, known under the code name SALVORG 34006, whose anion has the structure D

in particular its non-sodium salt, and its pharmaceutically acceptable salts, in US 2,378,829.

which is also described

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The compound of formula B, preferably in the form of the decodate salt, is the subject of a preferred use of the present invention and is also a preferred antithrombotic for the pharmaceutical compositions of the present invention in combination with a platelet aggregation anti-platelet agent (compound) as defined above. .

Platelet aggregation agents for use in the present invention belong to the group consisting of:

XXXVIII - SR 121787A or an analogue thereof:

(XXXVIH) where

-R Y is hydrogen, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, arylalkyl of 1 to 5 carbon atoms in the alkyl moiety, alkoxycarbonylalkyl of 1 to 3 carbon atoms in the alkyl moiety carbon or a carboxyalkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms;

-A ₃₈ is either a methylene group optionally mono- or disubstituted with an alkyl group having 1 to 5 carbon atoms; an alkoxycarbonyl group containing from 1 to 5 carbon atoms in the alkoxy moiety, an alkoxycarbonylalkyl group containing from 1 to 5 carbon atoms in the alkoxy moiety and an alkyl portion; a carboxyalkyl group containing from 1 to 5 carbon atoms in the alkyl moiety; phenyl or benzyl unsubstituted or substituted on the aromatic ring by C1 -C5 alkyl, C1 -C5 alkoxy, hydroxyl, halogen or trifluoromethyl; a pyridyl group; or an ethylene group;

₃ -R 8 is hydrogen or alkyl having 1-5 carbon atoms; an aryl or arylalkyl group containing from 1 to 5 carbon atoms in the alkyl moiety optionally substituted by a hydroxyl group, an alkoxy group containing 1 to 3 carbon atoms, a halogen atom, a trifluoromethyl group or an alkyl group containing 1 to 5 carbon atoms;

₃ -Y 8 is hydrogen; -COOR ₃₈ ^{2 2} wherein R38 is an alkyl group containing 1-5 carbon atoms, aryl or aralkyl group the alkyl portion contains 1-5 carbon uhlí35 to optionally substituted alkyl groups containing 1-5 carbon atoms; a group -COR38 ³ wherein _R38 ³ is an alkyl group containing 1-5 carbon atoms; or one of their salts as described in EP 719775.

The platelet aggregation agents used are glycoprotein IIb / IIIa antagonists and are selected from the group consisting of:

ethyl N- (1-ethoxycarbonylmethylpiperidin-4-yl) -N- {4- [4 - ({N-ethoxycarbonylimino) (amino) methyl} phenyl] thiazol-2-yl} -3-aminopropionate, referred to as SR 121787A, and pharmaceutically acceptable salts thereof and

N- (1-carboxymethylpiperidin-4-yl) -N- {4- [4 - {(amino) (imino) methyl} phenyl] thiazol-2-yl} -345 propionic acid and its pharmaceutically acceptable salts, such as trihydrochloride, referred to as SR 121566.

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The formulas SR 121787 and SR 121566 are given below:

CH ₂ CO ₂ COOC ₂ H _p

A selective Factor Xa inhibitor or in combination with an anti-platelet aggregation agent is particularly useful for the treatment or prophylaxis of pathological conditions such as cardiovascular or cerebral vascular diseases such as thromboembolic disorders associated with atherosclerosis or diabetes such as unstable angina, cerebral stroke, restenosis following angioplasty, endarterectomy, or deposition of metallic endovascular prostheses or such as thromboembolic disorders with retrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral vascular disease, hemodialysis, atrial fibrillation or bypass vascular aortas, in stable or unstable angina or in patients treated with a revascularization procedure at risk of thrombosis including percutaneous angioplasty, endovascular prostheses, vascular prostheses, aortocoronary passů.

Examples of pharmaceutically acceptable organic salts include oxalate, maleate, fumarate, methanesulfonate, benzoate, ascorbate, pamate, succinate, hexamate, bismethylenesalicylate, ethanedi20 sulfonate, acetate, propionate, tartrate, salicylate, citrate, gluconate, lactate, malate. mandelate, citraconate, aspartate, palmitate, stearate, itaconate, glycolate, p-aminobenzoate, glutamate, benzenesulfonate and theophylline acetate, as well as salts formed from amino acids such as lysine or histidine salts.

Examples of pharmaceutically acceptable inorganic salts include hydrochloride, hydrobromide, sulfate, sulfamate, phosphate and nitrate.

Neutralization of activated factor X (Xa) (with antithrombin III) can be catalyzed by pentasaccharide (PS) such as low molecular weight heparin. Unlike low molecular weight heparin, the pentasaccharide completely lacks activated thrombin. In addition, pentasaccharide challenge 30 modifies the hemostatic assay, and in particular the thromboplastin partial activation time (APTT) assay on human plasma, and unlike heparin, does not enhance ADP or collagen-induced platelet aggregation.

The antithrombotic effects of pentasaccharide have been demonstrated following intravenous (iv) and subcutaneous (sc) administration in various animal models in different types of induced thrombosis (rat venous model, arteriovanous shunt model in rats, Wessler model in rabbits) (Hobellen PMJ et al. , Tromb. & Haemost., 1996, 63 (2) 265-270 and Amar J. et al., Br. J. Haematol., 1990,

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76, 94-100). In terms of the risk of bleeding, blood loss at high doses of PS when tested in rats (21.7 mg / kg) is the same as seen with 200 units of anti-Xa / kg heparin, suggesting that PS only slightly increases blood loss compared to standard heparin or LMWH.

DETAILED DESCRIPTION OF THE INVENTION

To illustrate the present invention, and as an example, the results obtained during a study of enhancing the antithrombotic effect in rabbits by co-administering a selective Factor Xa inhibitor and a platelet aggregation agent are given below. SR 90107 / ORG 31540 (or PS) was selected as a selective factor Xa inhibitor and the platelet aggregation agent was selected from glycoprotein IIb / IIIa antagonists, in particular SR 1221787A.

The aim of this assay was therefore to determine the arterial antithrombotic effect when co-administered with antiXa, pentasaccharide SR 90107 / ORG 31540 and GPIIb / IIIa receptor antagonist, SR 121787A.

Male New Zealand rabbits weighing 2.7 to 3 kg were obtained from Lago breeding (France). They behaved under standard conditions.

Thrombus formation was induced by external electrical stimulation of the left carotid artery according to the method of Hladovec I. et al., (Experimental artetial thrombosis in rats with continous registration, Tromb. Diathes. Haemor. 1971; 26: 407-410). The rabbits were anesthetized with pentobarbital at 30 mg / kg i.v. Part of the left carotid artery was exposed and isolated with a piece of insulating film. Electrodes were placed on the artery. A partial contraction was performed on the artery causing a 20% reduction in flow. The artery was stimulated with a 2.5 mA current using a constant current stimulator for 3 minutes. Thrombotic occlusion was evaluated by continuous measurement of arterial blood flow using a NARCO electromagnetic flow meter. This measurement was made for 45 minutes when observed.

Freshly prepared solutions of SR 90107 / ORG 31540 and SR 121787A in brine were used for testing. SR 90107 / ORG 31540 solutions were injected via the IV route 5 minutes prior to thrombosis induction at a volume of 1 ml / kg. SR 121787A was administered by the oral route 2 hours earlier.

Results were calculated and expressed as a percent decrease in blood flow at different times relative to time 0. They are expressed together in Figure 1.

In control animals, the flow rate gradually decreased from 20.9 ± 2.1 to 3.8 ± 2.5 ml / min (n = 8; mean for 8 animals) after 15 minutes and 1.5 ± 1.4 ml / min. after 20 minutes. This value was then maintained until

45 minutes. SR 90107 / ORG 31540 at 300 nmol / kg had no effect on flow reduction.

600 nmol / kg 90107 / ORG 31540 reduced the flow slightly but not significantly.

SR 121787A administered 2 hours in advance as the active ingredient alone at an oral dose of 10 mg / kg did not significantly alter carotid passage, while 20 mg / kg almost completely inhibited this problem.

Co-administration of pentasaccharide SR 90107 / ORG 31540 and GPIIb / IIIa receptor antagonist SR 121787A, at doses that are separately inactive (300 nmol / kg iv and 10 mg / kg po, respectively) completely protect against flow reduction and therefore counteract thus induced arterial thrombosis.

In a toxicity study and in repeated tests (within 4 weeks at 10 mg / kg subcutaneously) no toxicological effect of SR 90107 / ORG 31540 was observed on any animal species, regardless of the concentration tested. SR 90107 / ORG 31540 is not mutagenic in the AMES test or DNA test.

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The use of a direct indirect selective Factor Xa inhibitor, oligosaccharide, in combination with an anti-platelet aggregation agent, is particularly advantageous for pathological conditions such as diseases of the cardiovascular and cerebrovascular system such as thromboembolic disorders associated with atherosclerosis or diabetes such as unstable angina, stroke, restenosis after angioplasty, enarectomy or fixation of metallic endovascular prostheses or such as thromboembolic diseases associated with thrombolysis, with heart attack, with dementia of ischemic origin, with peripheral arterial diseases, with hemodialysis and with fibrillar corticosteroids or with fibrillar corticosteroids bypass or for stable or unstable angina or for patients treated with a revascularization procedure at risk of thrombosis including percutaneous angioplasty, endovascular prosthesis, vascular prostheses, aortocoronary bypasses.

The use of an indirect selective factor Xa inhibitor, oligosaccharide, in combination with an anti-platelet aggregation agent does not increase the risk of bleeding.

The combination of an indirect selective factor Xa inhibitor, an oligosaccharide, and an anti-platelet aggregation agent can be formulated into pharmaceutical compositions which can be used by the oral or parenteral route, in particular by the subcutaneous route, as a mixture with conventional pharmaceutical ingredients.

Thus, in another embodiment, the present invention relates to pharmaceutical compositions comprising one or more indirect selective Factor Xa inhibitors acting through antithrombin III in combination with one or more compounds having anti-platelet aggregation activity as defined above and optionally one or more pharmaceutically acceptable carriers .

Preferred pharmaceutical compositions of the present invention comprise as an indirect factor Xa inhibitor methyl-O- (2-deoxy-2-sulfoamino-6-O-sulfo-α-D-glucopyranosyl) - (1-> 4) O- (PD-glucopyranosyluronic acid) - (1-> 4) -O- (2-deoxy-2-sulfoamino-3,6-di-O-sulfo30-α-D-glucopyranosyl- (1-> 4) -O- (2-O-sulfo-) α-L-idopyranosyluronic acid) - (1-> 4) -2-deoxy-2-sulfoamino-6-O-sulfo-α-D-glucopyranoside, whose anion has the structure B

or one of its pharmaceutically acceptable salts.

A further preferred class of pharmaceutical compositions comprises those comprising glycoprotein IIb / IIIa ethyl-N- (1-ethoxycarbonylmethylpiperidin-4-yl) -N- {4- [4 - {(N-methoxycarbonylimino) - (amino) methyl} phenyl] as an antagonist thiazol-2-yl} -3-aminopropionate or trihydro40 chloride N- (1-carboxymethylpiperidin-4-yl) -N- {4- [4 - {(amino) (imino) methyl} phenyl] thiazol-2yl} -3 -aminopropionic acids.

The pharmaceutical compositions of the present invention are preferably provided in the form of dosage forms containing a predetermined amount of active ingredients, as specified below. Uniform oral administration forms include tablets, gelatin capsules, powders, granules, microgranules.

Platelet aggregation agents can be formulated according to methods known to those skilled in the art. This also applies to a selective factor Xa inhibitor.

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When formulating combinations of active ingredients for the preparation of the pharmaceutical compositions of the present invention, account must be taken of the nature of the active ingredients making up the combination.

The oligosaccharide is preferably used as a selective inhibitor of factor Xa in the form of an addition salt, for example in the form of the sodium salt.

Typically, oligosaccharides in the form of their addition salts with pharmaceutically acceptable acids are not chemically incompatible with non-salt platelet aggregation agents. However, some of these are often used in the form of acid addition salts. In any case, it is preferable to maintain the active ingredients separately using techniques known in the literature.

The pharmaceutical compositions of the present invention are particularly useful in the treatment or prophylaxis of diseases such as cardiovascular and cerebrovascular diseases, such as thromboembolic diseases associated with atherosclerosis or diabetes such as unstable angina, stroke, restenosis following angioplasty, endarterectomy or metallic insertion endovascular prostheses or such as thromboembolic disorders with retrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral vascular disease, hemodialysis, atrial fibrillation or during the use of vascular prostheses, aortocoronary bypass grafts or stable or unstable angiomas thrombosis-related procedures including percutaneous angioplasty, endovascular prostheses, vascular prostheses, aortocoronary bypass grafts.

The combinations of the present invention may be formulated into pharmaceutical compositions for administration to mammals, including humans, for the treatment of the above diseases.

The combinations of the present invention may be used at daily doses of a selective Factor Xa inhibitor or platelet aggregation agent of 0.1 to 100 mg / kg body weight of the mammal to be treated.

In humans, the dose of each component may range from 1 to 500 mg per day, depending on the age of the patient being treated and the type of treatment: prophylactic or therapeutic. Preferably, the pentasaccharide is administered at doses of 0.30 mg to 30 mg per patient per day.

In the pharmaceutical compositions of the present invention, the active ingredients are usually formulated in dosage units containing 0.1 to 50 mg of said active ingredient per dosage unit.

The compositions of the present invention are formulated to be administered by a digestive or parenteral route and are provided in a variety of forms, such as injectable or oral solutions, sugar coated tablets, flat tablets or gelatin capsules. Preferred pharmaceutical compositions are injectable solutions.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, transmucosal, topical or rectal administration, the active ingredient may be administered to animals and humans in unitary forms for administration in admixture with conventional pharmaceutical carriers. Suitable unitary administration forms include oral administration forms such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, sublingual or buccal administration forms, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms, and forms for rectal administration.

When preparing a solid composition in the form of a tablet, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, acacia and the like. The tablets may be coated with sucrose or other suitable agent or may be coated

They may be treated such that they have prolonged or delayed activity and that they continuously release a predetermined amount of the active ingredient.

Gelatin capsules are obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into a soft or hard gelatin capsule.

The water dispersible powders or granules may contain the active ingredient in admixture with a dispersing or wetting agent or suspending agent, such as polyvinylpyrrolidone, as well as sweetening or flavoring agents.

For rectal administration, suppositories are used which are prepared with a binder melting at rectal temperature, such as cocoa butter or polyethylene glycols.

For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions are used which contain pharmacologically compatible dispersants and / or wetting agents, for example propylene glycol or butylene glycol.

For transmucosal administration, the active ingredients may be formulated in the presence of a promoter such as a bile salt, a hydrophilic polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, pectins, starches, gelatin, casein. acrylic acid esters and copolymers thereof, vinyl polymers or copolymers, vinyl alcohols, alkoxopolymers, polyethylene oxide polymers, polyethers or mixtures thereof.

The active ingredients may also be formulated in the form of microcapsules, optionally with one or more carriers or excipients.

The active ingredients may be provided in the form of a complex with a cyclodextrin, for example α-, β or γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl β-cyclodextrin.

One of the active ingredients, for example an oligosaccharide, a factor Xa inhibitor, can also be released from the balloon containing it and by the endovascular expander introduced into the vessel. The pharmacological activity of the active ingredient is thus not affected.

Preferably, the selective Factor Xa inhibitor is administered by the intravenous or subcutaneous route.

In the therapeutic combinations of the present invention, the pharmaceutical forms preferably comprise 8 to 30 mg of a selective factor Xa inhibitor and 10 to 200 mg of an anti-platelet aggregation compound.

Particularly preferred are combinations of 15 to 25 mg of a selective factor Xa inhibitor and 10 to 30 mg of an anti-platelet aggregation agent. Even more preferably, the pharmaceutical forms of the present invention comprise 20 mg of pentasaccharide, a selective factor Xa inhibitor, and 20 mg of an anti-platelet aggregation agent.

Claims (6)

PATENT CLAIMS Use of an oligosaccharide which is an indirect factor Xa inhibitor acting through antithrombin III, in combination with one or more compounds having anti-platelet aggregation activity, antagonizing glycoprotein IIb / IIIa and selected from the group consisting of: - ethyl N- (1-ethoxycarbonylmethylpiperidin-4-yl) -N- {4- [4 - {(N-ethoxycarbonylimino) iso (amino) methyl} phenyl] thiazol-2-yl} -3-aminopropionate, -N- (1-carboxymethylpiperidin-4-yl) -N- {4- [4 - {(amino) (imino) methyl} phenyl] thiazol-2-yl} -3-aminopropionic acid, and its pharmaceutically acceptable salts, for the preparation of drugs for the prevention and treatment of thrombo15 embolic arterial diseases. Use according to claim 1, wherein methyl-O (2-deoxy-2-sulfoamino-6-O-sulfo-α-D-glucopyranosyl) - (1-> 4) -O- (3) is used as the indirect factor Xa inhibitor. -D-glucopyranosyluronic acid) - (1-> 4) -O- (2-deoxy-2-sulfoamino-3,6-di-O-sulfo-αD-glucopyranosyl20 (1-> 4) -O- (2- O-sulfo-α-L-idopyranosyluronic acid) - (1-> 4) -2-deoxy-2-sulfoamino-6O-sulfo-α-D-glucopyranoside, whose anion has the structure B 25 or one of its pharmaceutically acceptable salts. Use according to claim 1 or 2, wherein ethyl-N- (1-ethoxycarbonyl) methylpiperidin-4-yl-N- {4- [4 - {(N-ethoxycarbonylimino)] is used as glycoprotein IIb / IIIa antagonist ( amino) methyl} phenyl] thiazol-2-yl} -3-aminopropionate or N- (1-carboxy-30-methylpiperidin-4-yl) -N- {4- [4 - {(amino) (imino) methyl} phenyl] hydrochloride thiazol-2-yl} -3-aminopropionic acid. 4. A pharmaceutical composition comprising an oligosaccharide which is an indirect inhibitor of factor Xa acting through antithrombin III, in combination with one 35 or more compounds having anti-platelet aggregation activity, antagonizing glycoprotein IIb / IIIa and selected from the group consisting of: - ethyl N- (1-ethoxycarbonylmethylpiperidin-4-yl) -N- {4- [4 - {(N-ethoxycarbonylimino) (amino) methyl} phenyl] thiazol-2-yl} -3-aminopropionate, -N- {1-carboxymethylpiperidin-4-yl) -N- {4- [4 - {(amino) (imino) methyl} phenyl] thiazol-2-yl} -40-aminopropionic acid, and pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable carriers. 45 Pharmaceutical composition according to claim 4, characterized in that it comprises methyl-O- (2-deoxy-2-sulfoamino-6-O-sulfo-α-D-glucopyranosyl) - (1-> 4) - O- (3-D-glucopyranosyluronic acid) - (1-> 4) -O- (2-deoxy-2-sulfoamino-3,6-di-O-sulfo-α-D-glucopyranosyl- (1-> 4) -O- (2-O-sulfo-α-L-idopyranosyluronic acid) - (1-> 4) -2-deoxy-2-sulfoamino-6-O-sulfo-α-D-glucopyranoside, the anion of which has the structure B or one or a pharmaceutically acceptable salt thereof. Use according to claim 1, wherein said medicaments are active in pathological conditions such as diseases of the cardiovascular or cerebral vascular system, such as thromboembolic diseases associated with atherosclerosis or diabetes, such as unstable angina, stroke, restenosis following angioplasty. , endarterectomy or insertion of metal endovascular prostheses, or such as thromboembolic disorders associated with retrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral vascular disease, hemodialysis, atrial fibrillation, or when using vascular prostheses, aortocoronary bypass or coronary bypass 15 stable or unstable angina or in patients treated with a revascularization procedure at risk of thrombosis, including percutaneous angioplasty, endovascular prostheses, vascular prostheses, aortocoronary bypasses.